Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.
Multiple myeloma (MM)2 is a plasma cell malignancy with a yearly incidence of 14,000 in the United States and accounts for 10% of deaths from hematological malignancies (1). Multiple myeloma remains incurable with a median survival of 3-5 years. Current therapeutic options extend longevity, but patients eventually succumb to the disease due to the development of drug resistance (2).Nucleoside analogues are antimetabolites that play a pivotal role in the treatment of a spectrum of hematological malignancies. Our laboratory has extensively characterized the novel purine nucleoside analogues 8-chloroadenosine and congener 8-aminoadenosine (8-NH 2 -Ado) (3-5), which are highly effective in tissue culture models of multiple myeloma as well as a spectrum of other hematological and solid cancers. 8-Chloroadenosine is currently in phase I clinical trial. The general mechanism of action of these antimetabolites involves RNA and/or DNA termination, ATP depletion, and subsequent induction of apoptosis (6), but a comprehensive analysis of their cellular effects has not been reported.In this study, we describe a novel feature in the mechanism of action of purine nucleoside analogue 8-NH 2 -Ado. We find that 8-NH 2 -Ado inhibits glucose consumption that is associated with an activation of autophagy. This ability to reduce glucose consumption is particularly important, given the dependence of many tumor cells on aerobic glycolysis and the ensuing increase in glucose consumption to meet energetic and biosynthetic demands. Normal cells typically rely on oxygen to metabolize glucose via the glycolytic and oxidative phosphorylation pathways to generate ATP. In contrast, many tumor cells demonstrate enhanced glycolysis and lactate production, utilizing the less efficient mode of ATP production even in the presence of oxygen (7). This phenomenon, termed aerobic glycolysis, was ...